As part of The Cancer Genome Atlas group characterizing head and neck cancer, we have identified components of the classical and alternative NF-kB, PI3K-mTOR, and Notch pathways as candidate genetic drivers for aberrant NF-kB activation and defects in death signaling. A clinical trial with PI3K-mTOR inhibitor rapamycin has completed accrual and published. A multi-center trial targeting IAPs in the classical TNF-NF-kB pathway in combination with re-irradiation has been approved and opened. Studies using a genome wide RNAi screen employing NF-kB reporter lines have identified potential drug targets promoting NF-kB activation, under investigation.